Sigma receptors are saturable, high affinity binding sites for several important classes of psychotropic drugs including typical antipsychotic, antidepressant, anticonvulsant, and psychotomimetic compounds. They are likely to contribute to the beneficial and/or side-effect profile of these compounds. Our laboratory has investigated several aspects of the molecular and cellular pharmacology of sigma receptors. Cytotoxic effects of sigma ligands on primary culture of central and peripheral nervous system: Sgma ligands produced alterations in the morphology of cells from cortex, cerebellum, thalamus, spinal cord, and superior cervical ganglion. Initial effects involved alterations of processes, followed by cell rounding or extreme swelling, and cell death. Neurons appeared to be more sensitive than non-neuronal cells which were present in the cultures. In cerebellum, BD737, reduced haloperidol, and fluphenazine produced initial effects at 10 micromol. after 7 days and at only 3 micromol. after 21 days. Several aryl ethylenediamines killed spinal cord neurons after 15 days at 3 micromol. These results have important implications for neuroleptic-induced tardive dyskinesia. Characterization of sigma receptors in clonal cell lines: Thirteen tumor-derived cell lines from various tissues were examined for the presence and density of sigma-1 and sigma-2 receptors. These included human MCF-7 breast adenocarcinoma, T47D breast ductal carcinoma, NCI-727 lung carcinoid, A375 melanoma, U-138MG glioblastoma, SK-N-SH neuroblastoma, ThP-1 leukemia, and LNCaP prostate. All cell lines tested were found to express very high densities of sigma receptors, suggesting a role in tumor biology. Characterization of novel ligands for sigma receptors: In an attempt to develop new sigma receptor radioligands for biochemical studies and in vivo SPECT imaging, a series of novel iodo-substituted benzamides was investigated for affinity at sigma-1 and sigma-2 receptors. Two compounds, N-[2-(piperidinylamino)ethyl]-4-iodobenzamide (IPAB) and (N- benzylpiperidin-4-yl)-4-iodobenzamide (4-IBP), were of particular interest. IPAB had high affinity and selectivity for sigma-1 receptors, whereas 4-IBP exhibited high affinity for both sigma-1 and sigma-2 receptors. In vivo imaging of tumors using sigma receptors as targets for imaging agents: The high density of sigma sites in tumor cell lines has suggested that sigma receptor-targeted radioligands could be used to image tumors in vivo utilizing PET or SPECT technology. Using [131]PAB, scintigraphic images of implanted melanoma and NCI-H1299 large cell lung carcinoma were produced in nude mice. Also, 4-[125]BP was shown to bind with high affinity to MCF-7 breast tumor cells. Thus, these compounds may have tumor diagnostic potential.